Therapeutic drugs have traditionally been administered orally or by injection. However, several pharmaceuticals now being developed are not easily administered via these methods. For example, many drugs, particularly peptides, are degraded by digestive enzymes and/or the acidity present in the gastrointestinal tract and cannot be taken orally. Additionally, many substances are not readily absorbed in the gastrointestinal tract due to the low permeability of the intestinal membrane to hydrophilic compounds. Thus, these drugs must be administered parenterally.
Injections, however, can be painful and must be given under sterile conditions to prevent the spread of AIDS and other infectious diseases. Furthermore, substances, such as insulin, administered subcataneously, show marked individual variability with respect to absorption See, e.g., Galloway, J. A., et al., Diabetes Care (1981) 4:366-376. Additionally, repeated injections, often necessary to control such chronic diseases as diabetes mellitus, can cause undesirable side effects such as scar-ring, irritation and localized edema. Therefore, patients often fail to comply with the strict regimen required to adequately treat such disorders, thus resulting in further medical complications. For instance, diabetic cataracts and retinopathy can occur in diabetics who fail to comply with a prescribed treatment plan.
Furthermore, several disorders are not amenable to self-help using injectables, although this is the most desirable method of treatment. For example, hypoglycemic crisis is preferably treated with intravenous, intramuscular or subcutaneous injections of glucagon or intravenous injection of glucose solutions. Patients experiencing a hypoglycemic episode cannot easily treat themselves with injections as their motor functions are impaired. However, treatment is crucial since prolonged hypoglycemia can lead to irreversible coma. Generally, patients must resort to eating sugar candies, dextrose tablets or paste in order to raise the blood glucose concentration. This method is less than desirable since the substances must travel to the intestine for absorption and timing is crucial in such a crisis.
Drugs have also been delivered intranasally via nasal drops, sprays and/or inhalers. However, the amount of drug that reaches the nasal mucosa and ultimately becomes absorbed into the systemic circulation can be less than optimal. Experimenters have used permeation-enhancing agents to aid absorption through the nasal mucosa. See, e.g., Hirai, S., et al., Intl. J. Pharmaceutics (1981) 9:173-184; Monkhouse, D. C., and Groves, G. A., Aust. J. Pharm. (1967) 48:S70-S75; Moses, A. C., Proceedings of Land O'Lake, (1986) 86, Merrimac, WI, Lecture Note, p. 6.
It is difficult, however, to achieve consistent drug distribution using these methods and delivery of a constant dose of drug intranasally is problematic. Medical practitioners have attempted to use a metered-dose mechanical spray pump in an effort to achieve constant delivery. However, drugs so delivered have been found to be unevenly distributed in the septal wall with little being found in the lateral wall. Mygind, N., et al., Rhinology (1978) XVI: 79-88.
Other modes of administration include buccal, vaginal, rectal, dermal and tracheal delivery, none of which have been enthusiastically adopted due to societal resistance and inconvenience.
The eye has several unique anatomical characteristics. It is protected physically by tough layers of blood-ocular barriers. Bito, L. Z., et al., The Ocular and Cerebrospinal Fluids, Academic Press, 1977, pp. 229-243. The cornea is composed of an aqueous phase, the stroma, sandwiched by two lipid layers, the epithelium and endothelium, respectively. Most biological systems possess the opposite orientation. The nasolacrimal duct drains tears and other substances from the eye and is lined with absorptive mucosa. Thus, substances delivered into the ocular cul-de-sac can enter the systemic circulation via the nasolacrimal system without significantly entering the eyes.
Drugs administered into the eye are generally intended for disorders of the eye itself and are not given to alleviate other systemic pathologies. However, much of the drug so administered is not absorbed by the eye, for reasons discussed above, and enters the systemic circulation via the nasolacrimal system. Often, the concentrations required to provide desired ophthalmic effects can result in undesirable drug loads for the systemic circulation and sometimes toxic side-effects. For example, epinephrine has been used to treat eye disorders however, the majority of instilled epinephrine enters the systemic circulation as a result of absorption through the nasolacrimal drainage system and has been reported to produce systemic alpha- and beta-adrenergic side effects. McClure, D. A., General Pharmacology, Toxicology, and Clinical Experience, ACS Symposium Series, The American Chemical Society (1975), Number 14. Thus, the use of eye drops to deliver ophthalmic drugs has been problematic.
Attempts to deliver other drugs through the eye have been made but have generally been ineffective. For example, corneal absorption of enkephalins in rabbits has been studied, and it was found that close to 100% of the enkephalins recovered in the corneal epithelium were in hydrolyzed form due to peptidase cleavage thereof. Lee, V. H. L., et al., J. Ocular Pharmacol. (1986) 2:345.
Insulin was delivered to the rabbit conjunctiva with variable effects. Christie, C. D., and Hanzal, R. F., J. Clin. Invest. (1931) 10:787. Furthermore, the rabbit eye is proportinately larger than the human eye when compared to body size. Thus, enough drug can be administered to the rabbit eye to elicit a systemic response. The human eye, on the other hand, being very small in comparison to the body, generally cannot accommodate the volume required in order to elicit an adequate response. Furthermore, when very concentrated drug solutions are administered to the eye to avoid the use of large volumes, the ocular tonicity is disrupted causing discomfort and eye irritation. For reviews of other systems and mechanisms of ocular drug delivery see Lee, V. H. L., Pharmaceutical Technology Apr. 1987:26 and Lee, V. H. L., Pharmacy International (1985) 6:135.
Drugs can be administered to the eye using a variety of methods. For example, controlled-release formulations have been used to deliver ophthalmic drugs to the eye for the treatment of eye diseases and infections. Such formulations include matrix-type drug delivery systems such as hydrophilic soft contact lenses, soluble ocular inserts and scleral buckling materials. Capsule-type drug delivery systems, such as the device Ocusert.RTM., have been used for the delivery of the anti-glaucoma agent, pilocarpine, to the eye. Implantable silicone rubber devices have been used in the treatment of intraocular malignancies. For a review of these sustained-release systems, see Ueno, N., et al., "Ocular Pharmacology of Drug Release Devices," in Controlled Drug Delivery, Stephen D. Bruck, ed., vol. II, chap. 4, CRC Press, Inc. (1983).